Blood Cells, Molecules and Diseases 53 (2014) 105109
Contents lists available at ScienceDirect
Blood Cells, Molecules and Diseases
j ourna l homepage: www.e lsev ie r .com/ locate /bcmdOutcome of early-treated type III Gaucher disease patientsNi-Chung Lee a, Yin-Hsiu Chien a, Siew-Lee Wong b, Jiunn-Ming Sheen c, Fuu-Jen Tsai d, Shinn-Forng Peng e,Joseph Hang Leung f, Mei-Chyn Chao g, Chia-Tung Shun h, Wuh-Liang Hwu a,a Department of Medical Genetics and Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwanb Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwanc Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwand Department of Pediatrics and Medical Genetics, China Medical University Hospital, Taichung, Taiwane Department of Radiology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwanf Department of Radiology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwang Department of Pediatrics, Kaohsiung Medical University Hospital and Department of Medical Genetics, Kaohsiung Medical University College of Medicine, Kaohsiung, Taiwanh Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, TaiwanAbbreviations: GD, Gaucher disease; GBA, acid -glument therapy. Corresponding author at: Department of Pediatrics
Taiwan University Hospital, 7 Chung-Shan South Road, T23314518.
E-mail address: email@example.com (W.-L. Hwu).
http://dx.doi.org/10.1016/j.bcmd.2014.05.0071079-9796 2014 Elsevier Inc. All rights reserved.a b s t r a c ta r t i c l e i n f oArticle history:Submitted 13 December 2013Revised 6 February 2014Accepted 14 May 2014Available online 28 June 2014
Communicated by: Ari Zimran
Keywords:Type IIIB Gaucher diseaseNeuropathicp.L444P mutationEnzyme replacement therapyLymphadenopathyMental retardationRecombinant human acid -glucosidase GBA (rhGBA) infusion is an effective therapy for non-neuropathic(type I) Gaucher disease (GD), but its effect on subacute neuropathic (type III) GD is still controversial. Themost common genotype for type III GD is homozygous c.1448TNC (p.L444P) mutation, and in this study, wetreated seven such patients starting from an early age (median 2.1 years; range 12.9 years). Before the startof treatment, all patients presented hepatosplenomegaly, anemia, and thrombocytopenia, but with no neurolog-ical signs. Normalization of hemoglobin levels and platelet numbers was achieved in all patients in one year.However, after a median treatment period of 7.6 years (2.212.0 years), two patients developed horizontalgazepalsy, onehad seizures, four demonstratedmental retardation, andfive showedkyphosis.Moreover, lymph-adenopathy in the neck, thorax, or abdomenwas observed in four patients. Therefore, the progression of neuro-logical symptoms in these patients probably reflected the neurologic natural history of type III GD. Residualsomatic symptoms, including kyphosis and lymphadenopathy, may be more common than what we thought.An additional treatment will be necessary to improve the outcome of type III GD.
2014 Elsevier Inc. All rights reserved.Introduction
Gaucher disease (GD) is a sphingolipid storage disease, resultingfrom a deficiency in -glucocerebrosidase (EC 220.127.116.11, acid -glucosidase, GBA) activity . A deficiency in GBA leads to accumulationof glucocerebroside inmacrophages (Gaucher cell) in the bonemarrow,liver, spleen, and brain. GD can be classified into 3 clinical types: type I,or the non-neuropathic form (MIM #230800); type II or the acute neu-ropathic form(MIM#230900); and type III, or the subacute neuropathicform (MIM #231000) . Patients with type I GD usually manifesthepatosplenomegaly with or without bone deformity/crisis duringadulthood. Enzyme replacement therapy (ERT) with recombinantcosidase; ERT, enzyme replace-
and Medical Genetics, Nationalaipei 100, Taiwan. Fax: +886 2human GBA (rhGBA) is an effective treatment for type I GD, which re-duces hepatosplenomegaly, increases hemoglobin levels and plateletcount, and increases bone mineral density . Patients with type II GDtypically exhibit neurodegeneration and hepatosplenomegaly beforeone year of age. ERT does not prevent neurodegeneration , andmost type II GD patients die before early childhood.
Type III GD was originally reported from the province ofNorrbotten in Sweden. At that time these patients exhibited bothvisceral and neurological manifestations from childhood to deathwhich commonly occur before they reach adulthood , but nowthey respond to ERT with increased well-being . The causativeGBA gene mutation is c.1448TNC (p.L444P) . Type III GD patientswith myoclonic epilepsy and other GBA gene mutations were also re-ported . The p.L444P mutation is the predominant mutation intype III GD . Patients with homozygous p.L444P mutation fre-quently manifested severe systemic involvements but only mildneurological abnormalities including supranuclear horizontal gazepalsy and/or other eye symptoms, mental retardation, and seizures.These patients have also been classified as having type IIIB GD ,
106 N.-C. Lee et al. / Blood Cells, Molecules and Diseases 53 (2014) 105109as a means to differentiate them from the earlier recognized type IIIpatients (now defined as type IIIA) and patients with progressiveheart valve calcification (type IIIC) .
Although rhGBA infusion is an effective therapy for type I GD,effects of ERT on type III GD patients were variable. The EuropeanTask Force for Neuronopathic GD has reviewed the largest cohort(55 patients) of type III GD (40 with homozygous p.L444P mutation). However, therewas considerable variation in the dose of ERT, aswell as an uneven distribution of risk factors including age, genotype,and splenectomy.
In this study, we described seven type III GD patients who had ahomogeneous genetic background (homozygous p.L444P mutation).We treated these patients from an early age but found that their neuro-logical symptoms developed gradually. Residual somatic symptoms,including kyphosis and lymphadenopathy, are also common.Methods
GBA activity was measured by 4-methylunbellyferal substrates, aspreviously described . Genotyping was performed as described inour previous publication . A total of seven GD patients who werehomozygous for the p.L444P mutation were analyzed in this study(Table 1). Patient 2 was born prematurely at gestational age 29 weekswith a birth weight of 1340 g. The median age of the seven patients atdiagnosis was 1.9 years and the median age at the start of ERT withCerezyme (Imiglucerase) was 2.1 years (Table 1). The dose of ERTused was 60 U/kg/2 weeks, with the exception of patient 2, whosedosage was increased to 120 U/kg/2 weeks when lymphadenopathywas found. The median treatment period was 7.6 years. Follow-up ex-aminations of these patients were performed according to the recom-mendations from the Gaucher Registry, including regular studies forhemogram, chitotriosidase activity, CCL18 levels, the skeletal system,sizes of the visceral organs, andmentality. The degree of thoracic kypho-sis was estimated by the traditional Cobb angle measured on lateralspine radiographs, and the definition of kyphosis was an angle 45.An intelligence quotient (IQ) was obtained by using theWechsler Intel-ligence Scale for Children. Data are presented as the means standarddeviations. Statistical analyseswere performed using the SPSS statisticalpackage, version 11.5. The Wilcoxon signed rank test was applied forTable 1Clinical characteristics of p.L444P/p.L444P Gaucher disease patients.
Patient no. 1 2 3
Gender M M FAge at diagnosis 10 m 1 y, 2 m 2 y, 7 mAge at ERT start 11 m 1 y, 2 m 2 y, 9 mGBA activitya 0.16 1.42 1.43ERT dose (U/kg/2 weeks) 60 60b 60Age at last survey 8 y, 5 m 4 y, 11 m 9 y, 2 mHemoglobin (g/dl)c 12.5 0.6 13.0 0.5 12.6 0.5Platelet (k/cumm) 162.2 31.7 182.6 62.4 213.0 41BMD (age, Z score) 0.581
(8.1 y,0.1)0.345(5.5 y,4.1)
Gaze palsy + Seizure Mental retardation (FIQ 88)d + (FIQ 66) Kyphosis (degree, age, area) + (48, 7 y 5 m, thoracic) + (53, 2 y 2 m,
Lymphadenopathye + (8 y 3 m,abdomen)
+ (3 y 6 m, neck,thorax, abdomen)
+ (7 y 8 mabdomen)
a GBA activity N N 5.1 nmol/mg/h.b Increased to 120 U/kg/2 weeks when lymphadenopathy occurred.c Hemoglobin and platelet values are mean (SD) after 1 year of treatment.d Scores of Verbal Comprehension index (VCI) and Processing Speed Index (PSI) were belowe Lymphadenopathy (age detected, location).statistical analysis before and after treatment. A p value less than 0.05was considered statistically significant.
Somatic responses to ERT
Hepatosplenomegaly and thrombocytopenia were observed in allpatients at the time of diagnosis, and five patients (except patient 6and 7) showed failure to thrive (Table 1). ThemeanHgB level increasedfrom 8.6 1.6 (g/dl) to 12.4 0.77 (g/dl) after 1 year of treatment(p = 0.028). The platelet count increased from 89.32 31.971.6(k/cumm) to 215.94 33.58 (k/cumm) after 1 year of treatment(p = 0.028). After a median treatment period of 7.6 years (2.212.0 years), none of them had an enlargement of the liver or spleen.Chitotriosidase activity decreased adequately in response to ERT,though a transient rise of chitotriosidase activities was noted duringthe period of drug short